Cancer of the urinary bladder remains a major cause of morbidity and mortality around the world (Kaufman D S, et al. Lancet. (2009) 18 374:239-49; Noon A P, et al. Nat Rev Urol. (2013) 10:67-8; Ploeg M, et al. World J Urol (2009) 27:289-93). Despite significant success of targeted anti-cancer therapy in other common solid tumors such as breast and lung cancer, patients with loco-regionally advanced and metastatic urothelial carcinoma (UC) have limited therapy options especially when chemoresistance develops to standard anti-cancer therapies (Gorin M A, et al. Postgrad Med. (2012) 124:28-36; Calabro F, et al. Eur Urol. (2009) 55(2):348-358).
The micropapillary variant of UC (MPUC) was first described in 1994 (Amin M B, et al. Am J Surg Pathol. (1994) 18:1224-32). Encompassing approximately 5% of all bladder cancers, MPUC is a clinically important lesion characterized by a distinctive histology featuring small micropapillae created by clusters of 4 to 5 cells across, peripherally situated nuclei and cytoplasmic vacuoles with a strong tendency to develop intra-lymphatic permeation or simulate lymphovascular involvement due to the production of peri-tumoral stromal retraction artifacts (Amin M B, et al. (1994) supra); Sangoi A R, et al. Am J Surg Pathol. (2010) 34:1367-76; Kamat A M, et al. Cancer (2007) 110:62-7; López J I, et al. Histopathology (1999) 34:561-2).
The diagnosis of MPUC harbors an adverse prognosis. Five year survival after diagnosis with metastatic urothelial carcinoma is small, pointing to the need for improved pharmacologic treatment of the disease. The standard cytotoxic regimen of MPUC is methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC), and it warrants improvement. It is well-accepted that the diagnosis of MPUC harbors an adverse prognosis and pathologists have strongly recommended that, even if the minority of a urinary bladder UC features a MPUC pattern, the diagnosis of MPUC is recommended to be made either outright or the tumor should be classified as UC with MPUC features (Amin M B, et al. (1994), supra; Sangoi A R, et al. (2010), supra; Kamat A M, et al. (2007), supra; López J I, et al. (1999), supra). Among the noteworthy clinicopathologic features of MPUC, is the association of metastatic disease at the time of diagnosis for a tumor with either no invasion or limited invasion of the bladder wall. This finding is similar to that observed for other micropapillary carcinomas occurring in other sites such as in the endometrium, breast and lung (del Carmen M G, et al. Gynecol Oncol. (2012) 127:651-61; Chen L, et al., Int J Surg Pathol. (2008) 16:155-63; Kamiya K, et al. Mod Pathol. (2008) 21:992-1001).
Given the highly aggressive nature of MPUC, the need exists for developing novel therapeutic approaches for treating micropapillary carcinomas, such as MPUC.